To prevent and/or treat disorders accompanied with a disorder of polyol metabolism (e.g. neuropathy, retinopathy, nephropathy, etc.) among disorders accompanied with diabetes, the development of representative inhibitors against aldose reductases FK366 represented by the following formula: ##STR4##
has been progressed.
To prepare the above FK366, 2,4-quinazolinedione derivative having a carboxyalkyl group represented by the formula (I): ##STR5##
is an important intermediate. As the process of preparing this intermediate, for example, the following processes have been reported [Chemistry Express, vol.8, no.9, p.761-764 (1993)]:
1: a process of heating N-alkylanthranilic acid with urea and closing the ring, PA1 2: a process of subjecting anthranylamide to introduction reaction of carbonyl group by means of phosgene, and the like, to give a quinazolinedione derivative having carboxyalkyl groups not only at the 1-position but also the 3-position, PA1 3: a process of subjecting a phenylurea derivative obtained by reaction between anthranilic acid and isocyanate to ring-closing reaction to give a quinazolinedione derivative having a carboxyalkyl group at the 3-position, not at the 1-position, PA1 4: a process of comprising: subjecting a quinazolinedione derivative obtained from 4-chloroanthranyl acid to silylation reaction to give a silylquinazoline derivative; selectively reacting the resulting silylquinazoline derivative at the 1-position with ethyl bromoacetate; and subjecting the reaction product to desilylation reaction to give a quinazolinedione derivative having an ethoxycarbonylmethyl at the 1-position. PA1 (i) an irritant alkylating agent must be used to selectively subject the quinazolinedione derivative to alkylation reaction at the 1-position of the derivative in the first step; PA1 (ii) because of alkylating of the 1-position of the derivative in the first step, it is required to subject the alkylated derivatives to the silylation reaction; and PA1 (iii) comparatively expensive anthranilic acid is used as a starting material. PA1 X.sup.1, X.sup.2 and X.sup.3 are independently a halogen atom; PA1 A is an alkylene group; PA1 R.sup.1 is a protected carboxy group; PA1 R.sup.2 is a group to be carboxy group by hydrolysis or oxidation; PA1 L is an acid residue) PA1 1 A step of introducing a carboxy protective group into the intermediate compound (I); PA1 2 without isolating the resulting reaction product, a step of reacting it with a dihalobenzyl derivative of the compound (III) to benzylate its 3-position group; PA1 3 without isolating the resulting reaction product, a step of subjecting it to elimination reaction of the carboxy protective group to give the final desired compound (V). PA1 1 A step of directly reacting the intermediate compound (I) with a dihalobenzyl derivative compound (III) to give the final desired compound (V). PA1 1 A step of reacting an amino acid derivative of the compound (VII) with 2,4-dihalobenzoic acid of the compound (VI) in the presence of a copper containing catalyst to selectively substitute a halogen at the 2-position of the compound (VI) to give the compound (VIII), PA1 2 a step of comprising: reacting the resulting compound (VIII) with cyanic acid or its salts or urea and subjecting the reaction product to ring-closing reaction to give the intermediate compound (I). PA1 1 A step of comprising: reacting an amine derivative of the compound (XI) with 2,4-dihalobenzoic acid of the compound (VI) in the presence of a copper containing catalyst to selectively substitute a halogen at the 2-position of the compound (VI) to give the compound (IX), PA1 2 a step of reacting the resulting compound with cyanic acid or its salts or urea to give the compound (X), PA1 3 a step of subjecting the resulting compound to hydrolysis reaction or oxidation reaction to give the intermediate compound (I). PA1 1 A step of introducing a carboxy protective group into the intermediate compound (I) (Protection reaction of carboxy groups) PA1 2 without isolating the resulting reaction product, a step of reacting it with a dihalobenzyl derivative of the compound (III) to benzylate its 3-position group (Benzylation at the 3-position) PA1 3 without isolating the resulting reaction product, a step of subjecting it to elimination reaction of the carboxy protective group to give the final desired compound (V) (Elimination reaction of carboxy protective group) PA1 1 A step of reacting an amino acid derivative of the compound (VII) with 2,4-dihalobenzoic acid of the compound (VI) in the presence of a copper containing catalyst to selectively substitute a halogen at the 2-position of the compound (VI) to give the compound (VIII) PA1 2 A step of comprising: reacting the resulting compound (VIII) with cyanic acid or its salts or urea and subjecting the reaction product to ring-closing reaction to give the intermediate compound (I)
However, the above process 1 to 3 are usually conducted at high temperature (150.degree. C. or more) and by means of toxic reagents (e.g. phosgene, isocyanate, etc.), and they have many problems about yield and handling from an industrial point of view. Furthermore, the above process 4, which is represented by the following reaction scheme: ##STR6##
includes a lot of problems about the operation as follows:
Furthermore, an alkylating agent to be used in the above alkylation must be used in combination with a solvent to increase the yield of the desired intermediate.
Accordingly, it has been required to provide a process, which is superior in handling and safety, facilitates waste disposal, and makes it possible to obtain the desired intermediate at low cost. It has also been required to provide a process capable of efficiently obtaining 3-dihalobenzyl-2,4-quinazolinedione derivative as a final desired product by using this intermediate.